DREADD not the designer compound Designer receptors exclusively activated by designer drugs (DREADDs) constitute a powerful chemogenetic strategy that can modulate nerve cell activity in freely moving animal preparations. Gomez et al. used radioligand receptor occupancy measurements and in vivo positron emission tomography to show that DREADDs expressed in the brain are not activated by the designer compound CNO (clozapine N-oxide). Instead, they are activated by the CNO metabolite clozapine, a drug with multiple endogenous targets. This may have important implications for the interpretation of results obtained with this popular technology. Science, this issue p. 503 Metabolically derived clozapine is the in vivo actuator of designer drug receptors expressed in the central nervous system. The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology posits the use of “designer receptors,” which are exclusively activated by the “designer drug” clozapine N-oxide (CNO). Nevertheless, the in vivo mechanism of action of CNO at DREADDs has never been confirmed. CNO does not enter the brain after systemic drug injections and shows low affinity for DREADDs. Clozapine, to which CNO rapidly converts in vivo, shows high DREADD affinity and potency. Upon systemic CNO injections, converted clozapine readily enters the brain and occupies central nervous system–expressed DREADDs, whereas systemic subthreshold clozapine injections induce preferential DREADD-mediated behaviors.

中文翻译：

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化学遗传学揭示：DREADD 通过转化氯氮平占据和激活

DREADD 不是由设计药物 (DREADD) 专门激活的设计化合物设计受体构成了一种强大的化学遗传策略，可以调节自由移动的动物制剂中的神经细胞活性。戈麦斯等人。使用放射性配体受体占据测量和体内正电子发射断层扫描显示大脑中表达的 DREADD 不会被设计者化合物 CNO（氯氮平 N-氧化物）激活。相反，它们被 CNO 代谢物氯氮平激活，氯氮平是一种具有多个内源性靶点的药物。这可能对解释使用这种流行技术获得的结果具有重要意义。科学，这个问题 p。503 代谢衍生的氯氮平是中枢神经系统中表达的设计药物受体的体内促动器。化学遗传技术 DREADD（专门由设计药物激活的设计受体）广泛用于远程操纵自由移动动物的神经元活动。DREADD 技术假定使用“设计受体”，这些受体仅由“设计药物”氯氮平 N-氧化物 (CNO) 激活。然而，CNO 在 DREADD 中的体内作用机制从未得到证实。全身药物注射后，CNO 不会进入大脑，并且对 DREADD 的亲和力较低。CNO 在体内迅速转化为氯氮平，显示出高 DREADD 亲和力和效力。全身注射 CNO 后，转化的氯氮平很容易进入大脑并占据中枢神经系统表达的 DREADD，而全身亚阈值注射氯氮平会诱导优先 DREADD 介导的行为。